Synthetic Process Improvement of Zolpidem Tartrate
An improved synthetic process of zolpidem tartrate(1)was developed.Glyoxylic acid(4)was reacted with acetic anhydride to obtain 2,2-diacetoxyacetic acid(5),which was chlorinated by thionyl chloride to generate 2,2-diacetoxyacetyl chloride(6).Then,6 reacted with dimethylamine chloride to provide N,N-dimethyl-2,2-diacetoxyacetamide(7).Finally,7 was hydrolyzed by pyridinium 4-toluenesulfonate to afford the key intermediate N,N-dimethyl-2-oxoacetamide(8).p-Methylacetophenone(2)was another starting material,and brominated with bromine,followed by the reaction with 2-amino-5-methylpyridine by"one-pot"method to synthesize 6-methyl-2-(4-methylphenyl)-imidazole[1,2-a]pyridine(3),which was converted into α-hydroxyzolpidem(9)via nucleophilic addition with 8,and then 9 was subjected to the reduction by chlorotrimethylsilane/NaI system to bring out zolpidem(10).Finally,the target compound 1 was obtained from 10 through salification with L-(+)-tartaric acid with an overall yield of 52.4％(based on 2)and the purity of 99.89％.The process was stable with simple operation and low cost,which was suitable for industrial production.
zolpidem tartratesedative-hypnoticssynthetic processpharmaceutical process
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